It has become clear that endoplasmic reticulum stress participates deeply in the onset of various intractable diseases, such as neurodegenerative diseases and diabetes. The present inventors have previously discovered a novel transcription factor localized in the endoplasmic reticulum, OASIS (Old Astrocyte Specifically-Induced Substance), which plays an important role in signaling to avoid the endoplasmic reticulum stress (Japanese Patent Publication (Kokai) No. 2005-52016A).
The OASIS protein is a one transmembrane type basic leucine zipper (bZIP) transcription factor belonging to a CREB (Cyclic AMP Response Element Binding protein)/ATF(Activating Transcription Factor) family, and its gene was identified as a gene expressed specifically in murine astrocytes after long-term culture, and the sequences of the gene and the protein have been analyzed (Honma Y. et al., Molecular Brain Research, 69: 93-103, 1999). Thereafter, the human-derived OASIS gene was isolated, whose nucleotide sequence and the amino acid sequence encoded thereby were both identified (Omori Y. et al., Biochem Biophysic Res Commun, 26: 293 (1): 407-7 (2002)).
The present inventors have previously discovered that, although the OASIS protein exists in a normal status on the endoplasmic reticulum membrane of glial cells, when endoplasmic reticulum stress is loaded on the glial cell, the OASIS protein is cleaved by the phenomenon of RIP (Regulated Intramembrane Proteolysis) in the membrane (Brown, M. S. et al., Cell, 100, 391-398, 2000); the cleaved fragments (containing a basic leucine zipper (bZIP) common in CREB/ATF transcription factors) are transported into the nucleus; and in the nucleus the cleaved fragments bind to ERSE (ER Stress Response Element) and CRE (Cyclic AMP Response Element) (Mori, K., Cell, 101, 451-454, 2000), thereby inducing the expression of GRP78, an ER stress resistant chaperone, and the like, and promoting the activation or expression of the OASIS protein, and as a result, the death of nerve cells caused by the ER stress can be inhibited, or neurodegenerative diseases may be cured (Japanese Patent Publication (Kokai) No. 2005-52016A).